Stevens-Johnson Syndrome

Table of Contents

  1. What is Stevens-Johnson Syndrome?
  2. The SJS–TEN Spectrum
  3. Causative Drugs and Triggers
  4. HLA Pharmacogenomics and Genetic Screening
  5. Pathophysiology: Granulysin and Keratinocyte Apoptosis
  6. Clinical Features and Prodrome
  7. Diagnosis: Nikolsky Sign and Skin Biopsy
  8. SCORTEN Prognostic Score
  9. Treatment: Supportive Care and Immunomodulation
  10. Ophthalmological Emergency
  11. Research Papers
  12. Connections
  13. Featured Videos

What is Stevens-Johnson Syndrome?

Stevens-Johnson Syndrome (SJS) is a rare but potentially fatal mucocutaneous hypersensitivity reaction characterized by widespread keratinocyte death, skin detachment, and severe erosions of multiple mucous membranes. It was first described by Albert Mason Stevens and Frank Chambliss Johnson in 1922 in two children with fever, stomatitis, and conjunctivitis — a clinical picture now recognized as the mucocutaneous inflammatory syndrome we understand today.

SJS belongs to a continuum of escalating severity: SJS (epidermal detachment less than 10% of body surface area), SJS/TEN overlap (10–30% detachment), and toxic epidermal necrolysis (TEN or Lyell syndrome) (greater than 30% detachment). The distinction is prognostic, not mechanistic — all represent the same immune-mediated keratinocyte destruction driven by cytotoxic lymphocytes and natural killer cells. TEN, at its most severe, resembles a full-thickness burn covering the majority of the body surface.

Incidence is low — approximately 1–6 cases per million people per year for SJS, 0.4–1.2 per million for TEN — but mortality is high: roughly 5–10% for SJS and 25–35% for TEN, reaching over 90% in patients with the highest SCORTEN prognostic scores. Drug reactions account for approximately 70–80% of adult SJS/TEN cases; infection (primarily Mycoplasma pneumoniae) accounts for most pediatric SJS cases.

The SJS–TEN Spectrum

The International Consensus Classification (Bastuji-Garin, 1993) defines the spectrum by the percentage of total body surface area (BSA) showing epidermal detachment — meaning frank denuded skin or skin that detaches with lateral pressure:

An important pediatric subset is SJS due to Mycoplasma pneumoniae (MP-SJS or MIRM — Mycoplasma-Induced Rash and Mucositis). Children with this form have prominent mucous membrane erosions (oral, ocular, urogenital) with minimal or absent skin detachment. Some experts propose separating MIRM from drug-induced SJS given the more benign course and different trigger.

Erythema multiforme (EM) is a related but distinct entity — typically self-limited, recurrent, predominantly caused by herpes simplex virus, with classic "true" target lesions (three zones: central dusky or necrotic core, pale edematous ring, erythematous periphery) and less severe mucous membrane involvement than SJS. The old term "EM major" for severe EM with mucosal involvement has been largely abandoned in favor of the SJS classification to avoid confusion.

Causative Drugs and Triggers

Drug reactions are the predominant cause of SJS and TEN in adults. The interval from first drug exposure to SJS onset is typically 1–3 weeks (the time needed for sensitization and immune expansion). On rechallenge or with an already-sensitized patient, onset may occur within 3–10 days. Recognizing the responsible drug and stopping it immediately is the single most important therapeutic intervention.

High-Risk Drug Classes

Infectious Triggers

Mycoplasma pneumoniae is the dominant infectious trigger, predominantly in children and young adults. SJS following Mycoplasma tends to have less skin detachment with more severe mucosal involvement. Herpes simplex virus (HSV) triggers erythema multiforme more commonly than SJS. Histoplasma, cytomegalovirus (CMV), and HIV infection have also been associated with SJS/TEN.

HLA Pharmacogenomics and Genetic Screening

One of the most striking advances in understanding SJS/TEN has been the discovery of specific HLA (human leukocyte antigen) alleles that confer extremely high risk for drug-specific reactions. These associations reflect the fact that the drug or its reactive metabolite must be presented by a specific MHC molecule to activate cytotoxic T cells.

Key HLA–Drug Associations

The mechanistic basis is direct: the drug (or a reactive metabolite) binds non-covalently to the peptide-binding groove of the specific HLA molecule, forming a pharmacological interaction (the "p-i concept") that mimics antigen presentation and activates cytotoxic T cells bearing specific T-cell receptors. This is distinct from classical drug haptenation.

Pathophysiology: Granulysin and Keratinocyte Apoptosis

The cellular mechanism of keratinocyte death in SJS/TEN has been substantially elucidated over the past two decades. Activated drug-specific cytotoxic CD8+ T lymphocytes (CTLs) and natural killer (NK) cells accumulate in the skin in response to the drug-HLA interaction. These effector cells kill keratinocytes through multiple pathways:

Granulysin — The Key Mediator

The landmark 2008 study by Chung and colleagues identified granulysin as the dominant soluble cytotoxin responsible for widespread keratinocyte death in SJS/TEN. Granulysin is a cationic cytolytic protein stored in secretory lysosomes of CTLs and NK cells. It is released upon target cell recognition and penetrates the keratinocyte membrane, triggering caspase-independent apoptosis via mitochondrial pathway disruption. Critically, granulysin was found in blister fluid at concentrations 4–10 times higher than perforin or granzyme B, and its concentration correlates directly with disease severity. In mouse models, injection of recombinant granulysin alone reproduced the skin detachment of SJS/TEN.

Additional Apoptotic Pathways

The end result — massive synchronous keratinocyte apoptosis across large areas of skin — is histologically visible as full-thickness epidermal necrosis with a clean dermal-epidermal separation, seen on skin biopsy as necrotic epidermis separating above an otherwise relatively normal dermis (in contrast to burns, where the dermis is also damaged).

Clinical Features and Prodrome

Prodromal Phase (Days 1–3)

SJS/TEN characteristically begins with a nonspecific flu-like prodrome that may be mistaken for a viral illness or drug side effect: fever (often greater than 39°C), malaise, sore throat, photophobia, burning eyes, and skin tenderness or dysesthesia. This prodrome precedes the skin eruption by 1–3 days. The early mucosal burning and photophobia are important warning signs — mucous membrane involvement in SJS/TEN nearly always precedes or accompanies the rash, unlike most other drug eruptions.

Cutaneous Eruption

The rash typically begins on the trunk and face, then spreads to involve the extremities. Initial lesions are dusky erythematous macules or atypical target lesions — flat, lacking the raised edematous ring of true erythema multiforme targets. These macules coalesce rapidly, and the centers of the lesions become purpuric or necrotic. Within 1–3 days, the epidermis begins to detach, starting with blister formation within the macules. The skin may feel painful and tender before visible blistering — patients often describe it as a "burning" or "raw" sensation under the skin. The Nikolsky sign is positive: lateral pressure on erythematous skin causes the epidermis to shear and separate laterally.

Mucous Membrane Involvement — Mandatory for SJS Diagnosis

Mucous membrane erosions are a defining feature of SJS and must be present. Involvement includes:

Diagnosis: Nikolsky Sign and Skin Biopsy

Clinical Assessment

SJS/TEN is primarily a clinical diagnosis. The key diagnostic features are:

The RegiSCAR (Registry of Severe Cutaneous Adverse Reactions) group developed validated scoring criteria using the above features to confirm SJS/TEN diagnosis and exclude mimics (e.g., staphylococcal scalded skin syndrome, which also shows Nikolsky positivity but is caused by exfoliatin toxin rather than immune-mediated keratinocyte death, and which spares mucous membranes).

Skin Biopsy

Biopsy of an early lesion (ideally within 24–48 hours) shows full-thickness epidermal necrosis with keratinocyte apoptosis at all levels of the epidermis, a sparse lymphocytic infiltrate at the dermal-epidermal junction, and subepidermal blister formation with little dermal inflammation. The necrotic epidermis rests on an otherwise relatively intact dermis — this contrasts with staphylococcal scalded skin syndrome, where the split is superficial (subcorneal) and epidermal necrosis is absent. Frozen sections of the detached "roof" can rapidly confirm full-thickness vs. superficial split.

Laboratory Evaluation

No blood test is diagnostic of SJS/TEN, but laboratory evaluation guides severity assessment and management:

SCORTEN Prognostic Score

SCORTEN (SCORe of Toxic Epidermal Necrolysis) is a validated prognostic scoring system developed by Bastuji-Garin and colleagues (2000) to predict in-hospital mortality for SJS/TEN. It is calculated from seven binary variables assessed within the first 24 hours of hospital admission:

  1. Age >40 years (1 point)
  2. Presence of malignancy (1 point)
  3. Heart rate >120 bpm (1 point)
  4. Initial BSA epidermal detachment >10% (1 point)
  5. Serum BUN >28 mg/dL (urea >10 mmol/L) (1 point)
  6. Serum bicarbonate <20 mEq/L (1 point)
  7. Serum glucose >252 mg/dL (14 mmol/L) (1 point)

SCORTEN score and associated predicted mortality:

SCORTEN should be recalculated on days 3 and 5 of admission, as BSA detachment typically peaks during this period and the metabolic variables evolve. It is used to guide triage decisions (transfer to burn unit), inform family communication, and stratify patients in clinical trials.

Treatment: Supportive Care and Immunomodulation

Step 1 — Immediate Drug Withdrawal

The single most impactful intervention is immediate identification and discontinuation of the causative drug. Each day of continued drug exposure is associated with increased BSA detachment and higher mortality. Where multiple drugs are implicated, all non-essential drugs should be stopped; the drug started most recently or most strongly associated with SJS/TEN (using tools like the ALDEN algorithm — Algorithm of Drug Causality in Epidermal Necrolysis) should be prioritized for discontinuation. The half-life of the offending drug also predicts how quickly the reaction will plateau after withdrawal.

Step 2 — Specialized Wound Care (Burn Unit)

Patients with SJS/TEN detachment greater than 10% should be transferred to a burn center or specialized dermatology intensive care unit. Management parallels burn care:

Immunomodulatory Therapies

Evidence for specific immunosuppressive therapies in SJS/TEN is limited by the rarity of the disease and absence of randomized controlled trials. The most studied options:

Ophthalmological Emergency

Ocular involvement in SJS/TEN is an ophthalmological emergency — the most feared long-term complication is permanent blindness from progressive conjunctival cicatrization (scarring), and the window for intervention to preserve vision is narrow.

Acute Ocular Manifestations

Symblepharon Formation

The most catastrophic acute complication is symblepharon — adhesion of the bulbar conjunctiva (over the eyeball) to the palpebral conjunctiva (lining the eyelids). Symblephara form rapidly as the inflamed conjunctival surfaces make contact and scar. Once established, symblephara restrict eye movement, distort lid anatomy, cause chronic dry eye, and expose the cornea to persistent abrasion. Aggressive early intervention is required to prevent their formation.

Ophthalmological Management

Even with optimal acute management, approximately 35% of SJS/TEN survivors have significant long-term ocular sequelae, and 3–10% are legally blind. Patients who survived SJS/TEN should be followed by an ophthalmologist long-term, as dry eye disease and conjunctival fibrosis can progress for years after the acute episode.

Research Papers

Key peer-reviewed studies on SJS/TEN pathogenesis, pharmacogenomics, and treatment. Each PMID link opens the study on PubMed.

  1. Chung WH, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004;428(6982):486. PMID 15057820
  2. Chung WH, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med. 2008;14(12):1343-1350. PMID 19029983
  3. Bastuji-Garin S, et al. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol. 2000;115(2):149-153. PMID 10951229
  4. Mockenhaupt M, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. J Invest Dermatol. 2008;128(1):35-44. PMID 17805350
  5. Halevy S, et al. Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol. 2008;58(1):25-32. PMID 17919772
  6. Nassif A, et al. Evaluation of T-cell-mediated blister formation in patients with toxic epidermal necrolysis: involvement of FasL and perforin pathways. J Invest Dermatol. 2004;123(5):964-971. PMID 15482487
  7. Schneck J, et al. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008;58(1):33-40. PMID 17919773
  8. Kirchhof MG, et al. Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine. J Am Acad Dermatol. 2014;71(5):941-947. PMID 25293716
  9. Chen P, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011;364(12):1126-1133. PMID 21428768
  10. Dodiuk-Gad RP, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: an update. Am J Clin Dermatol. 2015;16(6):475-493. PMID 26481651
  11. Shanbhag SS, et al. Acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis — the foundation for chronic disease. Am J Ophthalmol. 2019;206:172-190. PMID 30905660
  12. Choo KJL, Leow YH, Bigby M. Allopurinol hypersensitivity syndrome: a systematic review. Br J Dermatol. 2015;173(6):1560. PMID 26014403

Curated PubMed topic searches:

  1. PubMed: SJS/TEN treatment
  2. PubMed: HLA-B*15:02 carbamazepine
  3. PubMed: Granulysin mechanism
  4. PubMed: SCORTEN prognosis
  5. PubMed: Cyclosporine SJS
  6. PubMed: Ocular AMT in SJS
  7. PubMed: Mycoplasma SJS children
  8. PubMed: Allopurinol HLA-B*58:01

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Connections

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